DE1815804A1 - Process for the preparation of a new substituted anthranilic acid - Google Patents

Description

Dr. F. ZuiYisfein - Dr. E. Assmann Dr, R. Koenigsberger

Dipl. Phys. R. Holzhauer ο-ion *

Patent Attorneys 4 · - ^ / JD "

Munich 2, Bräuhaussfralje 4 / IU

Process for the production of a new substituted one

Anthranilic acid

The present invention relates to processes for the preparation of a new, substituted anthranilic acid and its Salts, these new substances themselves and medicinal products containing them, as well as their use.

The Ν- (α ₅ α, α, α ', α ^!, Α ¹ -hexafluoro-3,5-xyIyI) -anthranilic acid of the formula I.

f / - <\

CO - OH

(D

and their salts with inorganic and organic bases are so far not known. As has now been found, the compound of the formula I and its salts have valuable pharmacological properties Properties, especially anti-inflammatory (antiinf laminatorisehe), analgesic and antipyretic effectiveness

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favorable therapeutic index. The anti-inflammatory activity of the compound of the formula I can be demonstrated in animal experiments, for example in the case of oral administration, on UV erythema in guinea pigs and on bolus alba edema in rats (paws); continued in the cotton granuloma and wound granuloma test. The extremely low toxicity of the compound which can be prepared according to the invention has proven to be particularly advantageous over the known fluphenamic acid. The free acid and its salts ¹ with pharmaceutically acceptable inorganic and organic bases can be used orally, rectally or locally, and aqueous solutions of salts can also be used parenterally, especially intramuscularly, and intravenously or subcutaneously for the treatment of rheumatic, arthritic and other inflammatory diseases of warm-blooded animals .

The N- (α, α, α, α ¹ , α ¹ , α ¹ -hexafluoro-3,5-xylyl) -anthranilic acid of the formula I and its salts are prepared according to the invention by adding an o-halobenzoic acid or a salt thereof with α, α, α, α ', α ¹ , α'-hexafluoro-3,5-xylidine condensed, if desired liberating the acid of the formula I from an initially obtained salt and / or the free acid or the initially obtained salt into a salt or another salt converted with an inorganic or organic base. The condensation is preferably carried out in the warmth and in the presence of a copper-containing catalyst and an acid-binding agent in an organic solvent which is inert under the reaction conditions.

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leads. As ο-halobenzoic acid is in particular ο-chlorine or ο-bromo-benzoic acid used. As copper-containing catalysts For example, metallic copper with a large surface, such as copper powder or sponge copper, or copper compounds, such as copper (I) chloride or bromide, copper (II) chloride, copper bromide, sulfate, acetate, carbonate or oxide can be used. Suitable acid-binding agents are, for example, alkali carbonates, such as potassium carbonate, further copper (I) carbonate or copper (II) carbonate or tertiary organic amines. If a free o-halobenzoic acid is used as the starting material, it is preferred to use at least two equivalents of acid-binding agent and, if necessary, distilled that when the salt formation occurs released water alone or together with part of the solvent from before the main reaction. With essentially one equivalent of acid-binding agent, on the other hand, can be made by using a previously formed salt of an ο-halobenzoic acid, E.g. an alkali salt, such as the potassium salt, used as a starting material, since now only the one during the condensation released hydrogen halides is to be neutralized. The reaction temperatures are preferably between 100 and 200 °. If the condensation is carried out at normal pressure, it is used one therefore particularly such organic solvents as the reaction medium, that boil within or above this range. Examples are η-pentanol, isopentanol, n-butanol, dimethylformamide, Dimethyl sulfoxide or diethylene glycol dimethyl ether called. The main reaction can also take place in a closed

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barrel can be carried out and in this case also a lower one boiling solvent, e.g. a lower alkanol, such as ethanol, Isopropanol or methanol, find use as the reaction medium.

The Ν- (α, α, α, α ', α ¹ , α'-hexafluoro-3,5-xyIyI) -anthranilic acid of the formula I and its pharmaceutically acceptable salts are, as mentioned above, administered orally, rectally or parenterally . The daily doses range between 2 and 15 mg / kg, preferably 5-10 mg / kg body weight for adult patients. Suitable dosage unit forms, such as dragees, tablets, suppositories or ampoules, preferably contain 10-250 mg of said acid or a salt thereof with a pharmaceutically acceptable inorganic or organic base as active ingredient.

In unit dose form for oral use the content of active ingredient preferably between 107 =, and 907 =. To the In the manufacture of such unit dosage forms, the active ingredient is combined, for example, with solid, powdery carriers such as lactose, Sucrose, sox-bit, mannitol; Starches, such as potato starch, corn starch or amylopectin, also laminaria powder or citrus pulp powder; Cellulose derivatives or gelatin, if appropriate with the addition of lubricants, such as magnesium or calcium stearate or polyethylene glycols, to tablets or dragee cores. The latter is covered, for example, with concentrated Sugar solutions, which e.g. still include arabic gum, talc and / or May contain titanium dioxide, or with one in volatile organic solvents or solvent mixtures dissolved paint. Dyes can be added to these coatings, e.g.

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for labeling different doses of active ingredients. Push-fit capsules made of gelatin and soft, closed capsules made of gelatin and a plasticizer such as glycerine are suitable as further oral unit forms. The former contain the active ingredient preferably as granules mixed with lubricants such as talc or magnesium stearate, and optionally stabilizers such as sodium metabisulphite (Na ₂ S ₂ Oc) or ascorbic acid. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as liquid polyethylene glycols, it also being possible for stabilizers to be added.

As unit dose forms for rectal use, suppositories, for example, come into consideration, which consist of a combination of a Active ingredient with a suppository base on the basis of natural or synthetic triglycerides (e.g. cocoa butter), polyethylene glycols or suitable higher fatty alcohols consist, and gelatin rectal capsules, which contain a combination of the active ingredient with polyethylene glycols.

Ampoule solutions for parenteral, especially intramuscular or intravenous administration contain, for example, the free acid in a concentration of preferably 0.5-5% aqueous, with the help of customary solubilizers and / or emulsifiers and optionally stabilizers prepared dispersion, or preferably the aqueous solution of a pharmaceutically acceptable, water-soluble salt.

Other parenteral forms of administration are, for example lotions prepared with the usual auxiliaries, tinker

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doors and ointments for percutaneous use are considered.

The following regulations are intended to explain the production of a number of typical forms of application in more detail:

a) 1000 g of N- (α, α, α, α ¹ , α ¹ , α ¹ -hexafluoro-3,5-xylyl) -anthranilic acid are mixed with 550 g of lactose and 292 g of potato starch, the mixture with an alcoholic solution of 8 g of gelatin moistened and granulated through a sieve. After drying, add 60 g of potato starch, 60 g of ¹ EaIk and 10 g of magnesium stearate and 20 g of highly disperse silicon dioxide and press the mixture into 10,000 tablets, each weighing 200 mg and containing 100 mg of active ingredient, with partial notches for finer adjustment if desired the dosage can be provided.

b) 100 g of Ν- (α, α, α, α ', α ¹ , α'-hexafluoro-3,5-xylyl) -anthranilic acid are mixed well with 16 g of corn starch and 6 g of highly dispersed silicon dioxide. The mixture is moistened with a solution of 2 g of stearic acid, 6 g of ethyl cellulose and 6 g of stearin in about 70 ml of isopropyl alcohol and granulated through a sieve III (Ph. HeIv. V). The granulate is approx. Dried for 14 hours and then beaten through sieve HI-IIIa. It is then mixed with 16 g of corn starch, 16 g of talc and 2 g of magnesium stearate and pressed into 1000 coated tablets. These are coated with a concentrated syrup of 2 g of Lacca, 7.5 g of gum arabic, 0.15 g of color, 2 g of highly dispersed silicon dioxide, 25 g of talc and 53.35 g of sugar and dried. The coated tablets each weigh 260 mg and each contain 100 mg of active ingredient.

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c) 20.0 g of N- (a, a, a, a ¹ , a ', a ¹ -hexafluoro-3,5-xylyl) -anthranilic acid in a mixture of 232 ml of 1-n. Sodium hydroxide solution and 500 ml of boiled, pyrogen-free water are dissolved and the solution is made up to 2000 ml with the same water. The solution is filtered, filled into 1000 ampoules of 2 ml each and sterilized. A 2 ml ampoule contains 20 mg of Ν- (α, α, α, α ', α ¹ , α ¹ -hexafluoro-3,5-xyIyI) anthranilic acid as the active ingredient in the form of the sodium salt.

d) 50 g of N- (α, α, α, α ', α ¹ , α ¹ -hexafluoro-3,5-xylyl) anthranilic acid and 1950 g of finely grated suppository base (eg cocoa butter) are mixed thoroughly and then melted. 1000 suppositories of 2.0 g are poured from the melt, which is kept homogeneous by stirring. They each contain 50 mg of active ingredient.

e) 60.0 g polyoxyethylene anhydrosorbitol monostearate, 30.0 g anhydrosorbitol monostearate, 150.0 g paraffin oil and 120 g stearyl alcohol are melted together, 50.0 g Ν- (α, α, α, α ', α ¹ , α ¹ -hexafluoro-3,5-xylyl) anthranilic acid (finely powdered) are added and 590 ml of water preheated to 40 ° are emulsified. The emulsion is stirred until it cools to room temperature and filled into tubes.

The following example explains the preparation of Ν- (α, α, α, α ', α ¹ , α ¹ -hexafluoro-3,5-xylyl) anthranilic acid, but is not intended to restrict the scope of the invention in any way. The temperatures are given in degrees Celsius.

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¹ example
N- (α, α, α, α ', α', α'-hexafluoro-3,5-xylyl) anthranilic acid

A mixture of 710 g of o-chlorobenzoic acid and 298 g of 85% potassium hydroxide in 2500 ml of n-pentanol is heated to 160 ° (bath temperature) with stirring. About 1000 ml of n-pentanol are distilled off within 30 minutes. 1560 g of α, α, α, ο ¹ , a ^f , a'-hexafluoro-3,5-xylidine and 17 g of copper powder are then added and the mixture is refluxed for 15 hours. It is then cooled, the mixture is poured into a solution of 244 g of sodium carbonate in 2000 ml of water and the resulting solution is distilled with steam. After the excess α, α, α, α ', α', α'-hexa- · 'fluoro-3> 5-xylidine has been distilled off, activated carbon is added to the aqueous solution and filtered through Hyflo. The Piltrat is made with conc. Acidified hydrochloric acid. The precipitated crystals are filtered off and slurried in 10 liters of hot water. It is filtered off and the filter residue is crystallized from ethanol * The N- (α, α, cc, α ', α', α ¹ -hexafluoro-3,5-xylyl) -anthranilic acid melts at 195-197 °.

3.5 g of N- (α, α, α, α ', α ¹ , α ¹ -hexafluoro-3,5-xylyl) anthranilic acid are dissolved in 10 ml of 1-n. NaOH and evaporate the solution to dryness under 11 torr. The residue is crystallized from ether / petroleum ether. The sodium salt is obtained. Ν- (α, α, α, α ', α', α * hexafluoro-3,5-xylyl) anthranilic acid as colorless crystals with a melting point of 289-293 °.

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Claims (4)

Claims Process for the preparation of a new, substituted anthranilic acid and its salts, characterized in that Ν- (α, α, α, α ·, α ¹ , α'-hexafluoro-3 , 5-xylyl) anthranilic acid of the formula Γ σο - oh and their salts is prepared by dissolving o ~ halobenzoic acid or a salt thereof with α, α, α, α ', α', a'-hexafluoro ~ 3.5 ^r-X3 lidin condensed gewünsentenfalls liberated from a salt initially obtained acid and / or the free acid or the salt initially obtained is converted into a salt or another salt with an inorganic or organic base. 2. IT- (α, α, α, a ', α' _f a '-Hexaf luo r-3 »5-xylyl) -anthranilic acid of the formula I given in claim 1, and its salts with inorganic and organic bases, 3. Therapeutic preparations for the treatment of rheumatic, arthritic and other inflammatory diseases, characterized by a content of Ν ~ (α, α, α, α ', α ¹ , α ¹ -hexafluoro- ■ 909830/1512 3 »5-xylyl) anthranilic acid of the formula I specified in claim 1, or a pharmaceutically acceptable salt thereof with an inorganic or organic base, in combination with a inert carrier and optionally other additives. 4. Use of the compound according to Claim 2 as an anti-inflammatory, anti-inflammatory and anti-arthritis agent. 909830/1512